Antiplasmodial activity of nitroaromatic and quinoidal compounds: Redox potential vs inhibition of erythrocyte glutathione reductase

Prooxidant nitroaromatic and quinoidal compounds possess antimalarial activ ity, which might be attributed either to their formation of reactive oxygen species or to their inhibition of antioxidant enzyme glutathione reductase (GR, EC 1.6.4.2). We have examined the activity in vitro against Plasmodiu m falciparum of 24 prooxidant compounds of different structure (nitrobenzen es, nitrofurans, quinones, 1,1 ' -dibenzyl-4,4 ' -bipyridinium, and methyle ne blue), which possess a broad range of single-electron reduction potentia ls (ED and erythrocyte glutathione reductase inhibition constants (K-i(GR)) . For a series of homologous derivatives of 2-(5 ' -nitrofurylvinyl)quinoli ne-4-carbonic acid, the relationship between compound Ki(GR) and concentrat ion causing 50% parasite growth inhibition (IC50) was absent. For all the c ompounds examined in this study, the dependence of IC50 on their K-i(GR) wa s insignificant. In contrast, IC50 decreased with an increase in E-7(1) and positive electrostatic charge of aromatic part of molecule (Z): log IC50 ( muM) = -(0.9846 +/- 0.3525) - (7.2850 +/- 1.2340) E-7(1) (V) - (1.1034 +/- 0.1832) Z (r(2) = 0.8015). The redox cycling activity of nitroaromatic and quinoidal compounds in ferredoxin:NADP(+) reductase-catalyzed reaction and the rate of oxyhemoglobin oxidation in lysed erythrocytes increased with an increase in their E-7(1) value. Our findings imply that the antiplasmodial activity of nitroaromatic and quinoidal compounds is mainly influenced by their ability to form reactive oxygen species, and much less significantly by the GR inhibition. (C) 2001 Academic Press.